Drug delivery device and method

ABSTRACT

Many people need vascular access for procedures such as hemodialysis. It is desirable that this access remain open or patent for the entire duration of the course of treatments. A drug delivery device and methods of using the device are introduced that delivery drug to venous anastomosis of a synthetic vascular access shunt. In some embodiments this device serves as the shunt connecting the target artery and vein to create the vascular access shunt.

RELATED APPLICATIONS

Applicant claims the benefit of priority of prior, co-pending U.S.application Ser. No. 13/186,259, filed Jul. 19, 2011, the entirety ofwhich is incorporated herein by reference.

BACKGROUND

Vascular access is important for the treatment of some chronic diseasessuch as those requiring hemodialysis treatments. A vascular access siteshould be prepared before starting those kinds of treatments becausedoing this allows for easier removal and replacement of the patient'sblood during treatment. The access site should allow for continuous,high blood flow volumes. Common complications from vascular access sitesinclude infection and low blood flow because the access passageway hasclotted.

Arteriovenous (AV) fistulas or AV shunts are basic kinds of vascularaccess for hemodialysis. An AV fistula connects an artery to a vein in apatient (such as in the patient's forearm) and is useful because itcauses the vein to grow larger and stronger allowing easier access tothe blood system. The AV fistula is considered the best long-termvascular access for hemodialysis because it provides adequate bloodflow, lasts a long time, and has a lower complication rate than othertypes of access. If an AV fistula cannot be created, an AV shunt orvenous catheter may be needed.

An AV fistula requires planning because it takes time after surgery todevelop—usually several months. But properly formed fistulas are lesslikely to form clots or become infected than are other access methods.Also, properly formed fistulas may work longer than other kinds ofaccess—sometimes for years.

A synthetic arteriovenous shunt is another type of vascular access is.It connects an artery to a vein using a synthetic tube, or shunt,implanted in the patient's forearm, for example. The shunt becomes anartificial vein that can repeatedly receive a needle for blood accessduring hemodialysis. A shunt can be used sooner, 2 or 3 weeks afterplacement, than an AV fistula.

Compared with properly formed fistulas, shunts have more clotting andinfection problems and need more frequent replacement.

Both types of access typically fail by clotting, which almost alwaysstarts with hyperplasia of the vessel wall near the venous anastomosis.What is needed is a convenient way to deliver a drug to that regionwithout interfering with the function of the vascular access.

SUMMARY

Invention drug delivery devices are useful for delivering a drug or drugsolution from a drug reservoir through a vascular access shunt to avenous anastomosis of that vascular access shunt or vasculaturedownstream from, the vascular access shunt. In some embodiments, thedevice comprises regions of differing permeability: a more permeableregion and a less permeable region. In some embodiments, the ratio ofpermeability of the high permeability region to the low permeabilityregion ranges from 100:1 to 10:1, including any value between thoseratios. In some embodiments, the more permeable region separates thedrug reservoir from the vascular access shunt.

The more permeable region allows the drug to move from the drugreservoir to the vascular access shunt. In some embodiments, the drugreservoir is adapted to supply drugs, through the more permeable region,to the boundary layer of the laminarly flowing blood in the vascularaccess shunt.

The drug delivery devices of this invention also comprise an elongateportion with two ends that are adapted to connect to mammalianvasculature. These ends and the elongate portion compose the vascularaccess shunt portion of the drug delivery device.

In some embodiments, the vascular access shunt part of the drug deliverydevice comprises a region comprising a self-sealing material.

In some embodiments, the vascular access shunt or the drug reservoircomprises one or more of polyacrylates, polymethacryates, polyureas,polyurethanes, polyolefins, polyvinylhalides, polyvinylidenehalides,polyvinylethers, polyvinylaromatics, polyvinylesters,polyacrylonitriles, alkyd resins, polysiloxanes, and epoxy resins.

In some cases, the more permeable part is adapted to deliver drug to aboundary layer formed by the flow of blood through the vascular accessshunt near the venous anastomosis.

In some embodiments the drug is selected to treat hyperplasia in thevessel walls near the venous anastomosis of the vascular access shunt orto treat thrombosis or to interfere with the stenotic cascade in thevessels near the venous anastomosis of the vascular access shunt.Specifically, in some embodiments, the drug comprises any one or anycombination of heparin, antiproliferatives, antineoplastics,anti-inflammatories, anti-platelets, anticoagulants, antifibrins,antithrombins, antimitotics, antibiotics, antiallergics, antioxidants,or their mixtures, or any prodrugs, metabolites, analogs, homologues,congeners, functional derivatives, structural derivatives, or salts ofthese.

The outer wall of the device may comprise a self-sealing material, whichin some cases is adapted to allow replenishment of the reservoir. Oneway of replenishing drug in the drug reservoir is by directly injectingdrug into the reservoir.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts an embodiment of an invention drug delivery device.

FIG. 2 depicts a side view of the device of FIG. 1.

FIG. 3 depicts a cross-sectional view of an embodiment of an inventiondrug delivery reservoir.

FIG. 4 depicts an expanded view of the device shown in cross-section.

FIG. 5 is a schematic view of a prior art, synthetic vascular accessshunt.

FIG. 6 is an expanded view of the anastomosis region of the prior art,synthetic vascular access shunt of FIG. 5.

FIG. 7 depicts an embodiment of an invention device shown placed on theschematic view of FIG. 5.

FIG. 8 depicts a method of delivering drug to a venous anastomosis usingan embodiment of a drug delivery device of this invention wherein themethod includes a pre-filling step.

FIG. 9 depicts a method of delivering drug to a venous anastomosis usingan embodiment of a drug delivery device of this invention wherein themethod includes a percutaneous filling step.

FIG. 10 depicts a method of delivering drug to a venous anastomosisusing an embodiment of a drug delivery device of this invention whereinthe method includes a pre-filling step and a percutaneous filling step.

FIG. 11 depicts an alternative method of delivering drug to a venousanastomosis using an embodiment of a drug delivery device of thisinvention wherein the method includes two percutaneous filling steps afilling step and a refilling step.

DETAILED DESCRIPTION

The following description of several embodiments describes non-limitingexamples that further illustrate the invention. All titles of sectionscontained in this document, including those appearing above, are not tobe construed as limitations on the invention; but they are provided tostructure the illustrative description of the invention that is providedby the specification.

Unless defined otherwise, all technical and scientific terms used inthis document mean what one skilled in the art to which the disclosedinvention pertains commonly understands them to mean. The singular forms“a”, “an”, and “the” include plural referents unless the context clearlyindicates otherwise. Thus, for example, reference to “a fluid” refers toone or more fluids, such as two or more fluids, three or more fluids,etc. When an aspect is said to include a list of components, the list isrepresentative. If the component choice is specifically limited to thelist, the disclosure will say so. Moreover, listing componentsacknowledges that embodiments exist for each of the components and anycombination of the components including combinations that specificallyexclude any one or any combination of the listed components. Forexample, “component A is chosen from A, B, or C” discloses embodimentswith A, B, C, AB, AC, BC, and ABC. It also discloses (AB but not C), (ACbut not B), and (BC but not A) as embodiments, for example. Combinationsthat one of ordinary skill in the art knows to be incompatible with eachother or with the components' function in the invention are excludedfrom the invention, in some embodiments.

FIG. 1 depicts the drug delivery device 100 according to an embodimentof the invention. Device 100 comprises a vascular access shunt 135connected to a drug reservoir 150. An outer membrane or structure 120encloses drug reservoir 150. The structure 120 comprises an internalregion 121 consisting of the portion of structure 120 connected tovascular access shunt 135. The internal region 121 comprises morepermeable region 130 that is disposed between drug reservoir 150 andvascular access shunt 135. In some embodiments, the entire internalregion 121 comprises more permeable region 130. In other embodiments, asdepicted in FIG. 2, only part of internal region 121 comprises morepermeable region 130. The structure 120 also comprises an externalregion 122 consisting of the portion of structure 120 that is notconnected to vascular access shunt 135. In general, external region 122is less permeable than more permeable region 130. In some instances,external region 122 is referred to as a less permeable region.

FIG. 1 also shows artery 510 and vein 520 with phantom lines. Whendevice 100 is implanted into a patient, it sits between artery 510 andvein 520, creating an alternative path for blood to travel from theheart through artery 510 and back to the heart through vein 520. Thisimplantation creates an arteriovenous shunt.

As shown in FIG. 1, vascular access shunt 135 comprises two ends 105 forconnecting artery 510 and vein 520 when the device 100 is implanted intothe patient. These ends are adapted to connect to mammalian vasculature,which means that they have one or more of the following features:

-   -   They are correctly sized to be connected to the target        vasculature;    -   They comprise material compatible with connecting to the target        vasculature;    -   They are correctly shaped to be connected to the target        vasculature;    -   They comprise material that can be sutured to the target        vasculature; or    -   They have any other feature that one of ordinary skill in the        art would expect to provide the ability or improve on the        ability to connect the ends 105 to the target vasculature.

In some embodiments, vascular access shunt 135 and drug deliveryreservoir 150 are integral with one another or are a one-piece unit. Forexample, see FIG. 1. Drug delivery reservoir 150 connects to vascularaccess shunt 135. As seen FIG. 1, ends 105 and external region 122extend out away from vascular access shunt 135 substantially preventingany drug or drug solution contained in drug reservoir 140 from diffusingaway from vascular access shunt 135. More permeable region 130 contactswall 152 of vascular access shunt 135; this is also shown in FIG. 4.

In such embodiments, vascular access shunt 135 need not be morepermeable to the drug or drug solution, in some embodiments, the morepermeable portion of vascular access shunt 135 meets with more permeableregion 130. In some embodiments, the composite device is constructed sothat the more permeable portion of wall 152 and more permeable region130 are the same structure.

FIG. 3 shows drug delivery reservoir 150 in cross-section. As depicted,drug delivery reservoir 150 has internal region 121 and an externalregion 122. As discussed above, internal region 121 is disposed betweendrug reservoir 150 and vascular access shunt 135, which is not shown inthis figure. Drug reservoir 140 is the actual cavity within drugdelivery reservoir 150 that contains the drug or drug solution.

While the embodiment in FIG. 3 is shown with a substantially rectilinearshape, the shape is not important to the function of drug deliveryreservoir 150. Drug delivery reservoir 150 is sized appropriately toconnect to vascular access shunt 135.

External region 122 is substantially less permeable to the drug or drugsolution. In some embodiments, external region 122 is flexible, rigid,or semi-rigid. External region 122 may comprise a glass, polymer,rubber, ceramic, paper, cotton, or metal material. External region 122can be monolithic, molded, pressed, or machined material or can comprisea woven substrate including a tightly woven substrate.

In some embodiments, more permeable region 130 is substantially morepermeable than external region 122, or, in some embodiments, comprises aregion with substantial permeability. In some embodiments, substantiallymore permeable means that more permeable region 130 allows diffusionfrom drug reservoir 140 at a rate within a range of rates such thatneither too much or too little drug is delivered from device 100. Insome embodiments, too much drug being delivered means that the amount ofdrug delivered causes the drug concentration to exceed the maximumtherapeutic dosage. In some embodiments too much drug being deliveredmeans that the amount of drug delivered causes the drug concentration tobe high enough that the drug's toxic side effects substantially outweighthe drug's beneficial effects, as measured by an ordinarily skilledartisan. In some embodiments, too little drug being delivered means thatthe amount of drug delivered causes the drug concentration to fall belowthe minimum therapeutic dosage or to fall low enough that the drug doesnot cause any beneficial effect.

More permeable region 130 can be monolithic, woven, spun, etc. Morepermeable region 130 comprises a polymeric, rubber, glass, plastic,ceramic, or metallic material. Permeability can be achieved through anymethod known to those of ordinary skill in the art. For example,permeability can occur because of a physically open structure such as amicroporous structure or permeability can occur because the material'schemical or physicochemical nature causes transport across the material.Or permeability can be achieved through other methods.

For drug delivery reservoir 150, both the materials composing the morepermeable region and materials composing the less permeable regions canbe selected largely independently of each other, provided that if one ofthe regions comprises a construction that substantially impedespenetration by a hypodermic needle or similar object, then the otherregion should be constructed such that the material allows penetrationby a hypodermic needle or similar object. This exception applies toembodiments that are designed to be implanted and then later filled orrefilled with additional drug solution using percutaneous access.

Device 100 should be susceptible to filling at the treatment facility iffilling is not done at the manufacturing facility. This calls for someaccess to the drug reservoir. For instance, device 100 may have sidesthat can stand up to puncture by hypodermic needle and that can thenreseal themselves after the needle's withdrawal. In some embodiments,the device may contain a valve that can open or close in response topressure from a needle or catheter or other device. A Luer tip issuitable for some embodiments. Also, some device embodiments comprise askin or subcutaneous access port. All of these accesses are well knownto those of ordinary skill in the art and facilitate adding drug or drugsolution to the device.

In some embodiments, the ability to refill the drug reservoir allows fora smaller device to be used because then the device need not containenough drug or drug solution for the entire course of treatment.Moreover, after-implantation accessibility allows the physician tochange the drug or drug combination should he or she decide to do so.

Both the more permeable and less permeable region materials should becompatible enough with each other so that they can be joined together.FIG. 4 depicts drug delivery device 100 in cross-section. Vascularaccess shunt 135 is attached to drug delivery reservoir 150 with morepermeable region 130 disposed between drug delivery reservoir 150 andvascular access shunt 135. In this embodiment more permeable region 130substitutes for part of wall 152 of vascular access shunt 135. Inalternative embodiments more permeable region 130 connects directly towall 152. In those embodiments, wall 152 should have substantialpermeability to the drug or drug solution.

As above, FIG. 4 also depicts drug reservoir 140. Drug or drug solutiontravels from drug reservoir 140 through more permeable region 130, and,in some embodiments, wall 152, into the vascular access shunt 135.

FIG. 5 depicts a schematic view of a portion of the patient. Thepatient's skin 500 is shown. Artery 510 carries blood away from thepatient's heart, while vein 520 carries blood back to the heart. Shownbetween artery 510 and vein 520 is vascular access shunt 135. Vascularaccess shunt 135 connects to vein 520 at a downstream or venousanastomosis 540.

FIG. 6 shows an expanded view of venous anastomosis 540 of FIG. 5.Fibromuscular hyperplasia of the vessel wall causes most stenosisproblems, which is indicated on FIG. 6, as 650 at venous anastomosis540.

Vascular access shunt 135 or drug reservoir 150 may comprise anybiocompatible polymer or copolymer. Implantable medical devices may alsobe made of polymers that are biocompatible and biostable orbiodegradable, the latter term including bioabsorbable and bioerodable.

As used in this document describing some embodiments, “biocompatible”refers to a polymer that is not toxic or has minimal toxicity; a polymerthat does not injure living tissue or if it does injure living tissue,the injury is minimal and reparable; or does not invoke an immunologicalreaction in the tissue or if it does invoke an immunological reaction,the reaction is minimal and controllable. Also, the partially degradedpolymer and all polymer degradation products have a biologicalinteraction similar to the one described in this paragraph.

Among useful biocompatible, relatively biostable polymers are, withoutlimitation, polyacrylates, polymethacrylates, polyureas, polyurethanes,polyolefins, polyvinylhalides, polyvinylidenehalides, polyvinylethers,polyvinylaromatics, polyvinylesters, polyacrylonitriles, alkyd resins,polysiloxanes and epoxy resins.

Blends and copolymers of the above polymers may also be used and arewithin the scope of this invention. Based on these disclosures, thoseskilled in the art will recognize which implantable medical devices, andmaterials composing those devices, will be useful with this invention'sembodiments.

“Polymer,” “poly,” and “polymeric” refer to materials resulting from apolymerization reaction and are inclusive of homopolymers and all formsof copolymers, “Copolymers” include random, alternating, block, andshunt variations. Also, those of ordinary skill in the art recognizethat “terpolymer”, or polymers made up of more than three different mersare a subset of copolymers.

Examples of biostable polymers include, among other polymers,polytetrafluoroethylene, fluorinated ethylenepropylene, polyvinylidenefluoride, polyether urethanes, polycarbonate urethanes, urethanescontaining surface modifying additives where these additives providesilicone, hydrocarbon, polyethylene glycol, fluorocarbon orperfluorocarbon chains on the surface, polyurethanes withsurface-modifying end groups consisting of silicone, hydrocarbon,polyethylene glycol or perfluoropolymer chains, polyolefins such aspolyethylene and polypropylene, ethylene polymers such as ethylene vinylacetate, ethylene coacrylic acid and ethylene covinyl alcohol,polyimide, polyetheretherketone, polyaryletherketone, polysulfone,PARYLENE, PARYLAST, polyethlyene teraphthalate, polyethylene oxide,polyurethane, silicones, polyesters, polyolefins, polyamides,polycaprolactam, polyvinyl chloride, polyvinyl methyl ether, polyvinylalcohol, acrylic polymers and copolymers, polyacrylonitrile, polystyrenecopolymers of vinyl monomers with olefins (such as styrene acrylonitrilecopolymers, ethylene methyl methacrylate copolymers, ethylene vinylacetate), polyethers, rayons, cellulosics (such as cellulose acetate,cellulose nitrate, cellulose propionate, etc.), and any derivatives,analogs, homologues, salts, copolymers and combinations of these. Insome embodiments, the polymers are selected such that they specificallyexclude any one or any combination of any of the polymers taught in thisdocument.

Any coatings of device 100 or device 100 itself may be composed ofpolymers. Representative examples of such polymers include, among otherpolymers, any one or any combination of fluorinated polymers orcopolymers, e.g., poly(vinylidene fluorides), poly(vinylidenefluoride-co-hexafluoro propenes), poly(tetrafluoroethylenes), andexpanded poly(tetrafluoroethylenes); poly(propylenes);co-poly(ether-esters); poly(ethylene oxides)/poly(lactic acids);poly(alkylene oxalates); poly(phosphazenes); poly(sulfones);poly(N-vinyl pyrrolidones); poly(ethylene oxides);poly(aminocarbonates); poly(iminocarbonates); poly(anhydride-co-imides);poly(hydroxyvalerates); poly(urethanes); vinyl halide polymers andcopolymers, e.g., poly(vinyl chlorides); polyvinyl ethers e.g.,polyvinyl methyl ethers); poly(acrylonitriles poly(vinyl ketones);silicones; poly esters); poly(olefins); copolymers ofpoly(isobutylenes); copolymers of ethylene-alphaolefins; poly(L-lacticacids); poly(L-lactides); poly(caprolactones);poly(lactide-co-glycolides); poly(hydroxybutyrates);poly(hydroxybutyrate-co-valerates); poly(dioxanones); poly(orthoesters);poly(anhydrides); poly(glycolic acids); poly(glycolides);poly(D,L-lactic acids); poly(D,L-lactides); poly(glycolicacid-co-trimethylene carbonates); poly(phosphoesters); poly(phosphoesterurethanes); poly(vinyl aromatics), e.g., poly(styrenes); poly(lactides);poly(lactide-co-glycolide) copolymers; poly(vinyl esters), e.g.,polyvinyl acetates); copolymers of vinyl monomers and olefins, e.g.,poly(ethylene-co-vinyl alcohols) (EVALs); copolymers ofacrylonitrile-styrenes; ABS resins; copolymers of ethylene-vinylacetates; poi (trimethylene carbonates); poly(amides), e.g., Nylon 66and poly(caprolactams); alkyd resins; poly(carbonates);poly(oxymethylenes); poly(imides); polyester amides); poly(ethers)including poly(alkylene glycols), e.g., poly(ethylene glycols) andpolypropylene glycols); epoxy resins; polyurethanes; rayons;rayon-triacetates; biomolecules, e.g., fibrins; fibrinogens; starches;poly(amino acids); peptides; proteins; gelatins; chondroitin sulfates;dermatan sulfates (copolymers of D-glucuronic acids or L-iduronic acidsand N-acetyl-D-galactosamines); collagens; hyaluronic acids; andglycosaminoglycans; poly(iminocarbonates); poly(ethylenes); otherpolysaccharides, e.g., poly(N-acetylglucosamines); chitins; chitosans;celluloses; cellulose acetates; cellulose butyrates; cellulose acetatebutyrates; cellophanes; cellulose nitrates; cellulose propionates;cellulose ethers; carboxymethylcelluloses; or their derivatives,analogs, homologues, congeners, salts, or copolymers.

In these or other embodiments, the device further comprises atherapeutic agent. Throughout this disclosure, “drug”, “therapeuticagent”, and bioactive agent are used interchangeably unless the contextclearly indicates otherwise. In some embodiments, the drug reservoircontains therapeutic or bioactive agents. The bioactive agents can beany moiety capable of contributing to a therapeutic effect, aprophylactic effect, both a therapeutic and prophylactic effect, orother biologically active effect in a mammal. The agent can also havediagnostic properties. The bioactive agents include, but are not limitedto, small molecules, nucleotides, oligonucleotides, polynucleotides,amino acids, oligopeptides, polypeptides, and proteins. In one example,the bioactive agent inhibits the activity of vascular smooth musclecells. In another example, the bioactive agent controls migration orproliferation of smooth muscle cells to inhibit restenosis. Thefollowing types of therapeutic agents are found in some inventionembodiments: proteins, peptides, antiproliferatives, antineoplastics,antiinflammatories, antiplateletes, anticoagulants, antifibrins,antithrombins, antimitotics, antibiotics, antioxidants, antiallergics,or any prodrugs, metabolites, analogs, homologues, congeners, functionalderivatives, structural derivatives, salts, or combinations of these.Some of the groups, subgroups, and individual bioactive agents may notbe used in some embodiments of the present invention.

Any drug capable of treating, preventing, eliminating, or amelioratinghyperplasia is suitable for use in the practice of this inventionLikewise, any drug that prevents blood clotting is useful in thepractice of this invention. Also, any drug capable of stopping,preventing, reversing, or slowing the stenotic cascade that results instenosis of the autogenous or synthetic shunt is useful in the practiceof this invention. Moreover, various invention embodiments exist thatuse any one or any combination of these drugs. Any of the drugs or drugcombination of the previous paragraph can be combined or furthercombined with other drugs such as anti-proliferative drugs,anti-inflammatory drugs, pro healing drugs, or antithrombotic drugs.

Examples of suitable therapeutic and prophylactic agents includesynthetic inorganic and organic compounds, proteins and peptides,polysaccharides and other sugars, lipids, and DNA and RNA nucleic acidsequences having therapeutic, prophylactic, or diagnostic activities.Nucleic acid sequences include genes, antisense molecules that bind tocomplementary DNA to inhibit transcription, and ribozymes. Some otherexamples of other bioactive agents include antibodies, receptor ligands,enzymes, adhesion peptides, blood clotting factors, inhibitors or clotdissolving agents such as streptokinase and tissue plasminogenactivator, antigens for immunization, hormones and growth factors,oligonucleotides such as antisense oligonucleotides, and ribozymes andretroviral vectors for use in gene therapy.

Antineoplastics or antimitotics include, for example, paclitaxel(TAXOL®, Bristol-Myers Squibb Co.), docetaxel (TAXOTERE®, Aventis S.A.), methotrexate, azathioprine, vincristine, vinblastine, fluorouracil,adriamycin, mutamycin, doxorubicin hydrochloride (ADRIAMYCIN®, Pfizer,Inc.) and mitomycin (MUTAMYCIN®, Bristol-Myers Squibb Co.), or anyprodrugs, metabolites, analogs, homologues, congeners, functionalderivatives, structural derivatives, salts, or combinations of these.

Antiplatelets, anticoagulants, antifibrin, and antithrombins include,for example, aspirin, sodium heparin, low molecular weight heparins,heparinoids, hirudin, argatroban, forskolin, vapiprost, prostacyclin andprostacyclin analogues, dextran, D-phe-pro-arg-chloromethylketone(synthetic antithrombin), dipyridamole, glycoprotein IIb/IIIa plateletmembrane receptor antagonist antibody, recombinant hirudin, and thrombininhibitors (ANGIOMAX®, Biogen, Inc.), or any prodrugs, metabolites,analogs, homologues, congeners, functional derivatives, structuralderivatives, salts, or combinations of these.

Cytostatic or antiproliferative agents include, for example, actinomycinD, actinomycin IV, actinomycin I1, actinomycin X1, actinomycin C1, anddactinomycin (COSMEGEN®, Merck & Co., Inc. angiopeptin, angiotensinconverting enzyme inhibitors such as captopril (CAPOTEN® and CAPOZIDE®,Bristol-Myers Squibb Co.), cilazapril or lisinopril (PRINIVIL® andPRINZIDE®, Merck & Co., Inc.); calcium channel blockers such asnifedipine; colchicines; fibroblast growth factor (FGF) antagonists,fish oil (omega 3-fatty acid); histamine antagonists; lovastatin(MEVACOR®, Merck & Co., Inc); monoclonal antibodies including, but notlimited to, antibodies specific for Platelet-Derived Growth Factor(PDGF) receptors; nitroprusside; phosphodiesterase inhibitors;prostaglandin inhibitors; suramin; serotonin blockers; steroids;thioprotease inhibitors; PDGF antagonists including, but not limited to,triazolopyrimidine; and nitric oxide, or any prodrugs, metabolites,analogs, homologues, congeners, functional derivatives, structuralderivatives, salts, or combinations of these.

Antiallergic agents include, but are not limited to, pemirolastpotassium (ALAMAST®, Santen, Inc.), or any prodrugs, metabolites,analogs, homologues, congeners, functional derivatives, structuralderivatives, salts, or combinations of these.

Examples of anti-inflammatory agents including steroidal andnon-steroidal anti-inflammatory agents include tacrolimus,dexamethasone, clobetasol, or any prodrugs, metabolites, analogs,homologues, congeners, functional derivatives, structural derivatives,salts, or combinations of these.

Other bioactive agents useful in the present invention include, amongother bioactive agents, free radical scavengers; nitric oxide donors;rapamycin; methyl rapamycin; 42-Epi-(tetrazoylyl)rapamycin (ABT-578);everolimus; tacrolimus; 40-O-(2-hydroxy)ethyl-rapamycin;40-O-(3-hydroxy)propyl-rapamycin;40-O-[2-(2-hydroxy)ethoxy]-ethyl-rapamycin; tetrazole containingrapamycin analogs such as those described in U.S. Pat. No. 6,329,386;estradiol; clobetasol; idoxifen; tazarotene; alphainterferon; host cellssuch as epithelial cells; genetically engineered epithelial cells;dexamethasone; or any prodrugs, metabolites, analogs, homologues,congeners, functional derivatives, structural derivatives, salts, orcombinations of these.

Free radical scavengers include, but are not limited to,2,2′,6,6′-tetramethyl-1-piperinyloxy, free radical (TEMPO);4-amino-2,2′,6,6′-tetramethyl-l-piperinyloxy, free radical(4-amino-TEMPO); 4-hydroxy-2,2′,6,6′-tetramethylpiperidene-l-oxy, freeradical (4-hydroxy-TEMPO), hexamethyl-3-imidazolinium-1-yloxy methylsulfate, free radical; 4-carboxy-2,2′,6,6′-tetramethyl-1-piperinyloxy,free radical (4-carboxy-TEMPO); 16-doxyl-stearic acid, free radical;superoxide dismutase mimic (SODm) and any analogs, homologues,congeners, functional derivatives, structural derivatives, salts, orcombinations of these.

Nitric oxide donors include, but are not limited to, S-nitrosothiols,nitrites, N-oxo-N-nitrosamines, substrates of nitric oxide synthase,diazenium diolates such as spermine diazenium diolate and any analogs,homologues, congeners, functional derivatives, structural derivatives,salts, or combinations of these.

Other therapeutic substances or agents which may be appropriate includeimatinib mesylate, pimecrolimus, and midostaurin.

Other therapeutic substances or agents which may be appropriate includealpha-interferon, bioactive RGD, and genetically engineered epithelialcells.

The foregoing substances can also be used in the form of prodrugs orco-drugs thereof. The foregoing substances are listed by way of exampleand are not meant to be limiting. Other active agents which arecurrently available or that may be developed in the future are equallyapplicable.

Dosage or concentration of the bioactive agent required to produce afavorable therapeutic effect should be less than the level at which thebioactive agent produces toxic effects and greater than the level atwhich non-therapeutic results are obtained. The dosage or concentrationof the bioactive agent can depend upon factors such as the particularcircumstances of the patient; the nature of the trauma; the nature ofthe therapy desired; the time over which the administered ingredientresides at the vascular site; and if other active agents are employed,the nature and type of the substance or combination of substances.Therapeutic effective dosages can be determined empirically, for exampleby infusing vessels from suitable animal model systems and usingimmunohistochemical, fluorescent or electron microscopy methods todetect the agent and its effects, or by conducting suitable in vitrostudies. Standard pharmacological test procedures to determine dosagesare understood by one of ordinary skill in the art.

Ultimately, the physician determines what drug or drug combination, whatdosage, what delivery rate, etc. for treatments using invention deliverydevices. The dosage and delivery are linked in some embodiments. Also,these parameters influence the frequency the device will need to berefilled. Higher diffusion out of the drug reservoir may suggest morefrequent replenishment.

In some embodiments, the diffusion rate is controlled by thepermeability of more permeable region 130. Control over the permeabilityof more permeable region 130 to the chosen drug can control the rate ofdiffusion out of the drug reservoir 150 across the more permeable region130.

Permeability can be controlled by a variety of methods. In someembodiments, permeability is controlled by mechanical means. All otherthings being equal, a thicker layer of a particular material yields alonger dwell time before drug delivery begins and a slower overalldiffusion rate. Similarly mechanically, larger holes or passageways inthe permeable membrane correlate with faster diffusion out of the deviceacross the membrane.

In some embodiments, the permeability of the membrane is controlledchemically. Hydrophobic polymer membranes correlate with slowerdiffusion by hydrophilic drugs and faster diffusion by hydrophobicdrugs. In a related manner, hydrogel or hydrophilic polymer membranescorrelate with faster diffusion by hydrophilic drugs and slowerdiffusion by hydrophobic drugs.

Some embodiments use multiple strategies to control the drug diffusionrate. For instance, if the drug comprises microparticles, the diffusionof the microparticle out of the drug reservoir largely correlates withthe nature of the microparticle, such as the size of the microparticle.Once the microparticle diffuses out of the drug reservoir, the rate ofdrug diffusion out of or off of the microparticle comes into play. Thus,selection of a microparticle-based drug gives two or more degrees ofcontrol over the diffusion rate.

Finally, permeability can be altered simply by choosing a differentmembrane material having a lower or higher permeability, as desired.

In some embodiments, the exit region of the more permeable portion ofthe device is from 0-1 inch; 0-0.5 inch; or 0-0.125 inch away from theanastomosis.

As delivered, the drug diffuses through more permeable region 130 andinto vascular access shunt 135.

In some embodiments, drug delivery reservoir 150 is affixed to the outerwall of the shunt with an adhesive. The adhesive is any adhesive as oneof ordinary skill would recognize as useful in such an application.

Many factors go into designing an implantable medical device that issuitable for implantation to form a vascular access shunt. These factorsare well-known to ordinarily skilled artisans. Moreover, sometimes thesefactors are contradictory or improvement to one factor yields erosion ofother factors making a balance between the factors necessary. Anordinarily skilled artisan that makes a determination of the materialand form of an implantable medical device necessarily balances thosefactors. Making such a balance, in such a determination of the materialand form for a device of the current invention by an ordinarily skilledartisan is referred to as adapting the device for implantation to form avascular access shunt. A device designed in this manner is said to beadapted for implantation to form a vascular access shunt.

In some embodiments, “adapted for implantation to form a vascular accessshunt” means that one or more of the following adaptations have beenprovided to or purposely chosen for the device:

The device comprises a material that provides an acceptably low level offoreign body response;

The device comprises a shape that arranges or fixes the more permeableregion of the device in relation to the vascular access shunt to causedrug diffusion that is directional towards the vascular access shunt orhighly directional towards the vascular access shunt (highly directionalmeans 2-, 4-, 6-, 8-fold or greater diffusion in one direction ascompared to the opposite direction);

The device comprises a drug reservoir accessible from outside of thepatient (for example, accessible to a filling device);

The device comprises a skin port connected to, in communication with, orin fluid communication with a drug reservoir;

The device comprises a material strong enough to protect the drugreservoir;

The device comprises a material that improves the biocompatibility ofthe device with the internal body environment;

The device comprises a coating that improves the biocompatibility of thedevice with the internal body environment;

The device comprises a biocompatible material;

The device comprises a biocompatible polymer;

The device takes a shape to correctly sit or between the vessels thatare or are to be shunted together;

The device comprises a large enough drug reservoir to hold enough drugsuch that one of ordinary skill in the art would consider the use of thedevice worthwhile;

The device comprises a drug reservoir that is capable of holding greaterthan a 3, 2, or 1 week drug supply;

The device comprises a drug reservoir that is capable of holding greaterthan a 1-7 days of drug supply;

The device comprises a structure that allows the device to remain or tobe anchored substantially stationary within the body;

The device comprises a material that furnishes the device the ability towithstand being filled or refilled;

The device comprises a material that furnishes the device the ability towithstand being handling or to withstand implantation into the body;

The device comprises a high permeability region in which thepermeability remains high enough for drug delivery or elution for thelength of time the device remains within the body;

The device comprises a material that allows penetration of or connectionwith a filling device (for example, a hypodermic needle) thatsubstantially seals itself after removal of the filling device;

The device is constructed out of expanded polytetrafluoroethylene; or

The device comprises a material substantially free of undesirablematerials or substantially free of undesirable, elutable materials.

FIG. 7 shows an invention drug delivery device 100 implanted as avascular access shunt 135. Vascular access shunt 135 connects to artery510 and vein 520 through ends 105. The figure depicts venous anastomosis540 connecting between end 105 on the venous side of vascular accessshunt 135 and vein 520. As shown, drug delivery reservoir 150 lies nearthe arterial side of vascular access shunt 135. As drug moves out ofdrug reservoir 140, it enters vascular access shunt 135 and flows towardvenous anastomosis 540. Once in the vicinity of venous anastomosis 540,the drug treats the vascular tissue.

Drug Delivery

Since the drug enters into vascular access shunt 135 through its walls,the drug enters the boundary layer naturally set up by laminar bloodflow within the shunt. Within the boundary layer, the drug retains arelatively high concentration because in laminar flow conditions littlemixing of the fluid occurs as it flows through the conduit. As it movesdownstream, the drug does not mix with blood for a time, allowing thedrug to remain at a therapeutically significant concentration until thedrug reaches downstream or venous anastomosis 540. Therefore, thosetreating the patient can select the drug to impede stenosis of venousanastomosis 540, and the drug can be delivered to the anastomosiswithout delivery substantially interfering with the shunt.

In some embodiments, the drug can be selected to treat thrombosis or totreat fibromuscular hyperplasia or to otherwise interfere with thestenotic cascade before stenosis occludes the venous anastomosis andrenders useless vascular access shunt 135.

Drug delivery reservoir 150 is constructed such that more permeableregion 130 contacts the wall of vascular access shunt 135, at least inpart. The goal is to have drug diffuse out of drug reservoir 140 throughmore permeable region 130 and through the wall of vascular access shunt135. As the drug diffuses through the shunt wall into the boundary layerwithin the shunt, it ultimately arrives at venous anastomosis 540.Therefore, the arrangement of external region 122 and more permeableregion 130 should accentuate the directionality of the diffusion fromdrug reservoir 140.

In some embodiments drug reservoir 140 is adapted to supply drug throughthe more permeable region 130 to the boundary layer of laminarly flowingblood in the vascular access shunt 135. In some embodiments adapted tosupply drug through the more permeable region 130 to the boundary layerof laminarly flowing blood in the vascular access shunt 135 means havingany structure or property that one of ordinary skill in the art wouldexpect the cause the device to be better able to supply drug to thelaminarly flowing blood in venous access shunt 135, such as:

The material of the drug reservoir 140 that context the drug or drugsolution is compatible with the drug or drug solution;

The drug reservoir 140 contains no or fewer interior barriers to theflow of drug or drug solution;

The drug reservoir 140 is substantially impermeable to drug or drugsolution except at more permeable regions;

The drug delivery device 100 is substantially stable to chemical orphysical attack by the environment of the body;

The drug reservoir 140 can be refilled without substantially affectingthe structural integrity of drug delivery device 100;

The drug delivery device 100 is substantially impermeable to fluids ormaterials of the environment of the body; or

Any other feature or change that one of ordinary skill in the art wouldmake or incorporate into the device to improve the device's ability tosupply drug.

Use of the device can be further understood by referencing the followingmethods.

FIG. 8 depicts an embodiment of a method of delivering a drug to venousanastomosis 540 with pre-filling step 800 comprising filling device 100with a drug or drug-containing solution. In some embodiments, thisfilling occurs by inserting a hypodermic needle into drug reservoir 140.The outer part of device 100 should be constructed of a material thatallows only minimal leakage through the hypodermic needle penetrationpoint once the needle has been withdrawn. In that sense, the materialthrough which the needle passes during this filling step isself-sealing. The method also comprises implanting step 810 comprisingimplanting device 100 to form a vascular access shunt 135 after thedevice has been filed. Some embodiments of these methods have removingstep 820 comprising removing device 100 from the patient when drugreservoir 140 is empty or when the patient no longer needs device 100.

FIG. 9 depicts an embodiment of a method of delivering a drug to venousanastomosis 540 comprising implanting step 810 comprising implantingdevice 100 to form a vascular access shunt 135 before device 100 hasbeen filed. This step is followed by percutaneous-filling step 900comprising filling device 100 with a drug or drug-containing solutionafter device 100 has been implanted. In some embodiments,percutaneous-filling step 900 comprises inserting a hypodermic needlethrough the patient's skin into drug reservoir 140 and operating theattached syringe to deposit drug or drug solution into drug reservoir140. Some embodiments of these methods have removing step 820 comprisingremoving device 100 from the patient when drug reservoir 140 is empty orwhen the patient no longer needs the device.

FIG. 10 depicts an embodiment of a method of delivering a drug tovascular access shunt 135 with prefilling step 800 comprising fillingdevice 100 with a drug or drug-containing solution. The method alsocomprises implanting step 810 comprising implanting device 100 to form avascular access shunt 135 after the device has been filed. Someembodiments of these methods have refilling step 1000 comprisingrefilling device 100 when drug reservoir 140 is depleted. In someembodiments, refilling step 1000 comprises inserting a hypodermic needlethrough the patient's skin into drug reservoir 140 and operating anattached syringe to deposit drug or drug solution into drug reservoir140. Other embodiments use other methods of refilling the drug similarto using a hypodermic needle and syringe couple.

FIG. 11 depicts an embodiment of a method of delivering a drug to venousanastomosis 540 comprising implanting step 810 comprising implantingdevice 100 to form a vascular access shunt 135 before device 100 hasbeen filed. This step is followed by percutaneous-filling step 900comprising filling device 100 with a drug or drug-containing solutionafter device 100 has been implanted. In some embodiments,percutaneous-filling step 900 comprises inserting a hypodermic needlethrough the patient's skin into drug reservoir 140 and operating theattached syringe to deposit drug or drug solution into drug reservoir140. Other methods of filling the drug similar to using a hypodermicneedle are used by other invention embodiments. Some embodiments ofthese methods have refilling step 1000 comprising refilling device 100when drug reservoir 140 is depleted. In some embodiments, refilling step1000 comprises inserting a hypodermic needle through the patient's skininto drug reservoir 140 and operating the attached syringe to depositdrug or drug solution into drug reservoir 140. Other embodiments useother methods of refilling the drug similar to using a hypodermic needleand syringe couple.

In addition to refilling drug reservoir 140 as described above, otherembodiments exist that use other types of drug or drug solutionreplenishment. For example, the reservoir may comprise a Luer-typefitting for mating with a corresponding Luer-type fitting on areplenishment device.

As discussed elsewhere in this document, filling can occur either beforeimplantation or after implantation. When filling occurs beforeimplantation, filling can be immediately before implantation, such aswithin 0 to 360 minutes before implantation. In some embodiments, thedrug reservoir is filled with drug before the device is shipped from themanufacturing facility. But filling this long before use raises a drugstability problem that can diminish the expected shelf life of thedevice. While this problem is not insurmountable, it can be avoided byfilling the device near the time the device is to be implanted. Thedevice without any drug or drug solution has a much longer shelf lifethan an already filled device. Filling can also occur after thephysician has implanted the device. When done at that time, filling canbe very similar to refilling.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from theembodiments of this invention in its broader aspects and, therefore, theappended claims are to encompass within their scope all such changes andmodifications as fall within the true, intended, explained, disclose,and understood scope and spirit of this invention's multitudinousembodiments and alternative descriptions.

Additionally, various embodiments have been described above. Forconvenience's sake, combinations of aspects composing inventionembodiments have been listed in such a way that one of ordinary skill inthe art may read them exclusive of each other when they are notnecessarily intended to be exclusive. But a recitation of an aspect forone embodiment is meant to disclose its use in all embodiments in whichthat aspect can be incorporated without undue experimentation. In likemanner, a recitation of an aspect as composing part of an embodiment isa tacit recognition that a supplementary embodiment exists thatspecifically excludes that aspect. All patents, test procedures, andother documents cited in this specification are fully incorporated byreference to the extent that this material is consistent with thisspecification and for all jurisdictions in which such incorporation ispermitted.

Moreover, some embodiments recite ranges. When this is done, it is meantto disclose the ranges as a range, and to disclose each and every pointwithin the range, including end points. For those embodiments thatdisclose a specific value or condition for an aspect, supplementaryembodiments exist that are otherwise identical, but that specificallyexclude the value or the conditions for the aspect.

Finally, headings are for the convenience of the reader and do not alterthe meaning or content of the disclosure or the scope of the claims.

What is claimed is:
 1. A method, comprising: filling a reservoir with adrug, wherein the reservoir is enclosed between an external region andan inner membrane of a structure, wherein the structure is coupled withan outer surface of a vascular access shunt, and wherein the innermembrane is more permeable than the external region; and implanting thevascular access shunt in a patient, the vascular access shunt having awall and an inner lumen, wherein the wall includes a substantiallypermeable region between the outer surface and the inner lumen such thatthe drug moves from the reservoir through the inner membrane and thesubstantially permeable region into the inner lumen.
 2. The method ofclaim 1, wherein filling the reservoir includes pre-filling thereservoir with the drug before implanting the vascular access shunt. 3.The method of claim 1, wherein filling the reservoir includes fillingthe reservoir with the drug after implanting the vascular access shunt.4. The method of claim 3, wherein filling the reservoir is performedpercutaneously through the patient's skin.
 5. The method of claim 4,wherein filling the reservoir includes refilling the reservoir with thedrug.
 6. The method of claim 5, wherein refilling the reservoir isperformed percutaneously through the patient's skin.
 7. The method ofclaim 1, wherein filling the reservoir includes injecting the drug intothe reservoir through a self-sealing material.
 8. The method of claim 7,wherein the self-sealing material includes a valve openable in responseto pressure.
 9. The method of claim 8, wherein the valve includes aluer-type fitting.
 10. The method of claim 1, wherein implanting thevascular access shunt includes connecting a plurality of ends of thevascular access shunt to the patient's vasculature such that the drugmoves from the inner lumen into the patient's vasculature.
 11. Themethod of claim 10 further comprising treating hyperplasia at ananastomosis located where one of the plurality of ends connects to thepatient's vasculature.
 12. The method of claim 11 further comprisingremoving the vascular access shunt from the patient's vasculature. 13.The method of claim 1, wherein the inner membrane includes a polymermembrane.
 14. The method of claim 13, wherein the polymer membraneincludes a woven polymer.
 15. The method of claim 13, wherein thepolymer membrane includes a hydrophobic polymer.
 16. The method of claim13, wherein the polymer membrane includes a hydrophilic polymer.
 17. Themethod of claim 1, wherein the ratio of the permeability of the innermembrane to the external region is in a range of 10:1 to 100:1.
 18. Themethod of claim 1, wherein the drug includes at least one of heparin,antiproliferatives, antineoplastics, anti-inflammatories,anti-platelets, anticoagulants, antifibrins, antithrombins,antimitotics, antibiotics, antiallergics, or antioxidants.
 19. Themethod of claim 18, wherein the drug includes a microparticle carrier.20. The method of claim 19, wherein the microparticle carrier is sizedto diffuse through the inner membrane at a rate such that the reservoirsupplies the drug to the patient for at least one week.